Reprogramming axonal behavior by axon-specific viral transduction

B. A. Walker, U. Hengst, Hyung Joon Kim, N. L. Jeon, E. F. Schmidt, N. Heintz, T. A. Milner, S. R. Jaffrey

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The treatment of axonal disorders, such as diseases associated with axonal injury and degeneration, is limited by the inability to directly target therapeutic protein expression to injured axons. Current gene therapy approaches rely on infection and transcription of viral genes in the cell body. Here, we describe an approach to target gene expression selectively to axons. Using a genetically engineered mouse containing epitope-labeled ribosomes, we find that neurons in adult animals contain ribosomes in distal axons. To use axonal ribosomes to alter local protein expression, we utilized a Sindbis virus containing an RNA genome that has been modified so that it can be directly used as a template for translation. Selective application of this virus to axons leads to local translation of heterologous proteins. Furthermore, we demonstrate that selective axonal protein expression can be used to modify axonal signaling in cultured neurons, enabling axons to grow over inhibitory substrates typically encountered following axonal injury. We also show that this viral approach also can be used to achieve heterologous expression in axons of living animals, indicating that this approach can be used to alter the axonal proteome in vivo. Together, these data identify a novel strategy to manipulate protein expression in axons, and provides a novel approach for using gene therapies for disorders of axonal function.

Original languageEnglish (US)
Pages (from-to)947-955
Number of pages9
JournalGene Therapy
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2012

Fingerprint

Axons
Ribosomes
Genetic Therapy
Proteins
Sindbis Virus
Neurons
Viral Genes
Wounds and Injuries
Protein Biosynthesis
Proteome
Epitopes
Genome
RNA
Viruses
Gene Expression
Therapeutics
Infection

Keywords

  • Sindbis
  • axon regeneration
  • viral vector gene transfer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Walker, B. A., Hengst, U., Kim, H. J., Jeon, N. L., Schmidt, E. F., Heintz, N., ... Jaffrey, S. R. (2012). Reprogramming axonal behavior by axon-specific viral transduction. Gene Therapy, 19(9), 947-955. https://doi.org/10.1038/gt.2011.217

Reprogramming axonal behavior by axon-specific viral transduction. / Walker, B. A.; Hengst, U.; Kim, Hyung Joon; Jeon, N. L.; Schmidt, E. F.; Heintz, N.; Milner, T. A.; Jaffrey, S. R.

In: Gene Therapy, Vol. 19, No. 9, 01.09.2012, p. 947-955.

Research output: Contribution to journalArticle

Walker, BA, Hengst, U, Kim, HJ, Jeon, NL, Schmidt, EF, Heintz, N, Milner, TA & Jaffrey, SR 2012, 'Reprogramming axonal behavior by axon-specific viral transduction', Gene Therapy, vol. 19, no. 9, pp. 947-955. https://doi.org/10.1038/gt.2011.217
Walker BA, Hengst U, Kim HJ, Jeon NL, Schmidt EF, Heintz N et al. Reprogramming axonal behavior by axon-specific viral transduction. Gene Therapy. 2012 Sep 1;19(9):947-955. https://doi.org/10.1038/gt.2011.217
Walker, B. A. ; Hengst, U. ; Kim, Hyung Joon ; Jeon, N. L. ; Schmidt, E. F. ; Heintz, N. ; Milner, T. A. ; Jaffrey, S. R. / Reprogramming axonal behavior by axon-specific viral transduction. In: Gene Therapy. 2012 ; Vol. 19, No. 9. pp. 947-955.
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